Elucidating the Role of Transcription Factor 21 (TCF21) in Kidney Development – Implications for Congenital Anomalies of the Kidney and Urinary Tract

Congenital anomalies of the kidney and urinary tract (CAKUT) is the leading cause of chronic kidney disease and of end stage renal failure in children worldwide. Although the pathogenesis of CAKUT is incompletely understood and heterogenous, it has been shown that many cases arise from mutations in genes important to kidney development - transcription factors particularly. Nevertheless, in spite of significant scientific breakthroughs in the understanding of kidney development in recent years, in clinical practice, therapy of CAKUT continues to rely on supportive care. Previous work by our lab showed that Transcription Factor 21 (TCF21), a basic helix-loop-helix transcription factor that controls development of the heart and the lung, is also critical in nephrogenesis. Our lab also showed that TCF21’s absence from mouse kidney leads to CAKUT. Hence, TCF21-mediated signal cascade may hold promise in finding new therapeutic targets in CAKUT. It is still unclear however, what are the mechanisms by which TCF21 affects kidney development, what signaling pathways it controls, and how it interacts with known key mediators of nephrogenesis. Preliminary results of the current project implicate glial cell line-derived neutrotrophic factor (GDNF), a key molecule in ureteric bud branching, and its inhibitor BMP4 as mediators of TCF21’s action in CAKUT. This implies that TCF21 is mechanistically linked to a fundamental process in kidney development - branching morphogenesis. Our central hypothesis is that TCF21 control of BMP4 is critical for spatiotemporal regulation of GDNF and therefore for ureteric bud branching and mesenchymal-to-epithelial transition. In the current project, we will utilize total and conditional knockout mouse models of Tcf21, nephron progenitor cells and kidney organoids to answer the following questions: 1. What are the different renal phenotypes related to Tcf21 deletion? 2. How does TCF21 affect molecular signaling in nephron progenitor cells? 3. What are TCF21’s direct gene targets? We believe that these findings will lay the foundation to diagnostic and therapeutic approaches CAKUT and will add to the mounting data on molecular pathways in nephrogenesis. Additionally, since kidney development and regeneration share underlying pathways, we expect that evidence from this project will be pertinent to tissue engineering in-vitro and may assist in replacement of injured kidney tissue. The candidate’s long-term career goal is to become an independently funded researcher with expertise in kidney development and the molecular mechanisms in CAKUT. The short-term goal is to elucidate specific mechanisms by which TCF21, as a model of key transcription factor in nephrogenesis, exerts its action in kidney development. This innovative work will be mentored by Dr. Susan Quaggin, an internationally acclaimed developmental nephrologist.